Brain, Vol. 122, No. 4, 675-686,
April 1999
© 1999 Oxford University Press
Specific temporoparietal gyral atrophy reflects the pattern of language dissolution in Alzheimer's disease
1 Prince of Wales Medical Research Institute, Randwick, 2 Faculty of Medicine, University of New South Wales, 3 Centre for Education and Research on Ageing, Concord Hospital, University of Sydney, 4 School of Communication Sciences and Disorders, University of Sydney, Australia and 5 Department of Psychology, University of Exeter, UK
Correspondence to:
J. A. Harasty, PhD, Prince of Wales Medical Research Institute, High Street, Randwick, NSW 2031, Australia E-mail: J.Harasty{at}unsw.edu.au
 |
Abstract |
|---|
 Top Abstract IntroductionMethodResultsDiscussionReferences |
|---|
The aim of this study was to determine the topography and degree of atrophy in speech and language-associated cortical gyri in Alzheimer's disease. The post-mortem brains of 10 patients with pathologically confirmed Alzheimer's disease and 21 neurological and neuropathological controls were sectioned in serial 3 mm coronal slices and grey and white matter volumes were determined for specific cortical gyri. All Alzheimer's disease patients had prospectively documented impairments in verbal and semantic memory with concomitant global decline. The cortical regions of interest included the planum temporale, Heschl's gyri, the anterior superior temporal gyri, the middle and inferior temporal gyri, area 37 at the inferior temporoparietal junction, areas 40 and 39 (supramarginal and angular gyri) and Broca's frontal regions. Although most patients had end-stage disease, the language-associated cortical regions were affected to different degrees, with some regions free of atrophy. These included Broca's regions in the frontal lobe and Heschl's gyri on the superior surface of the temporal lobe. In contrast, the inferior temporal and temporoparietal gyri (area 37) were severely reduced in volume. The phonological processing regions in the superior temporal gyri (the planum temporale) were also atrophic in all Alzheimer's disease patients while the anterior superior temporal gyri were only atrophic in female patients. Such atrophy may underlie the more severe language impairments previously described in females with Alzheimer's disease. The present study is the first to analyse the volumes of language-associated gyri in post-mortem patients with confirmed Alzheimer's disease. The results show that atrophy is not global but site-specific. Atrophied gyri appear to reflect a specific network of language and semantic memory dissolution seen in the clinical features of patients with Alzheimer's disease. Females showed greater atrophy than males in the anterior superior temporal gyri.
Alzheimer's disease; language; cortex, gyral atrophy; semantic memory
|
Introduction |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionReferences |
|---|
Alzheimer's disease is a debilitating progressive disease which gradually affects all aspects of cognition and behaviour, including aspects of semantic memory and semantic knowledge (Hodges and Patterson, 1995
; Desgranges et al., 1996). Most patients with confirmed Alzheimer's disease appear to have fluent speech with poor semantic content and comprehension (Appell et al., 1982; Cummings et al., 1985; Code and Lodge, 1987; Hart, 1988). Selective loss of the appropriate use and recall of word meanings and object naming and recognition occurs particularly in discourse (Hodges et al., 1992; Bayles et al., 1993; Hodges and Patterson, 1995) while phonology (sound structure), syntax (sentence order and structure) and grammar are usually well preserved until later in the disease process (Obler and Albert, 1981; Appell et al., 1982; Au et al., 1988).
The brain substrate of the seemingly selective and specific loss of types of language functions in Alzheimer's disease is intriguing. Two competing theories for this pattern of semantic breakdown have been proposed. One theory, argued by Gonnerman et al. (1997), suggests that semantic categories are differentially affected as features within a single distributed network are eroded through widespread damage of the brain. Although atypical cases with more selective neocortical involvement have emerged (Ross et al., 1996), it is theorized by many that such early differences are gradually subsumed towards a more generalized widespread brain pathology at death. The second theory argues that different brain regions underlie different categories of semantic knowledge (Garrard et al., 1998). This second theory is substantiated by neuropsychological data showing a disproportionate loss of natural kinds of knowledge compared with artefactual knowledge in the majority of patients with probable Alzheimer's disease (Garrard et al., 1998). The categories of natural kinds of knowledge and artefactual knowledge have been refined since the seminal work on category disassociation by Warrington and McCarthy (1983). These authors found that a global aphasia could occur where knowledge of living things such as flowers and animals could be retained, while at the same time knowledge and object matching of non-living items such as tools and furniture (artefacts) was severely impaired. Specific category impairments have been demonstrated in many additional cases since this work (for a brief review, see Gonnerman et al., 1997). The second paradigm suggests that the loss of discrete aspects of language processing and production, such as specific category knowledge, reflects a progressive loss of certain brain areas rather than generalized loss over a distributed neural network.
This question has not yet been directly addressed in human post-mortem brains from patients with pathologically confirmed Alzheimer's disease. In patients with probable Alzheimer's disease, lobar and blood flow studies indicate that pathology and hypometabolism are most accentuated in the temporolimbic areas and temporoparietal association cortices, often with a left hemisphere focus (Jack et al., 1992; Killiany et al., 1993; Soininen et al., 1994, 1995; Deweer et al., 1995; Shear et al., 1995; Laakso et al., 1995; Lehtovirta et al., 1995; Nagy et al., 1996; Bartenstein et al., 1997; Vargha-Khadem et al., 1997; Grossman et al., 1998; Hirono et al., 1998). This suggests some anatomical specificity to the functional deficits. While these areas are particularly associated with naming (Daum et al., 1996; Grossman, 1996; Lambon Ralph et al., 1997), smaller, anatomically discrete cortical regions are known to be more specialized for selective aspects of language, such as the planum temporale for phonological processing (Damasio and Damasio, 1992; Damasio et al., 1996; Aboitiz and Garcia, 1997). In particular, the primary hearing region, Heschl's gyrus, does not show tangle formation (Esiri et al., 1986).
Few studies have examined the multiple, specialized cortical language-associated regions for differential involvement in Alzheimer's disease. In addition, the majority of studies have analysed patients with mild to moderate disease. The purpose of the current study was to use post-mortem volumetric techniques to investigate whether specific atrophy occurs in cortical gyri with known language-associated functions in end-stage Alzheimer's disease. Data were collected in order to examine questions about the two competing theories on semantic breakdown in Alzheimer's disease. The involvement of specific gyral atrophy at an end stage in the disease process would suggest that different brain regions are affected differently and that this reflects the differences in semantic (and general cognitive and language system) breakdown seen clinically. Alternatively, if end-stage pathology reflects widespread generalized damage in all the language-associated gyri, then this may relate to a more diffuse type of network involvement, as suggested by Gonnerman et al. (1997). The roles of variables such as gender and hemisphere are also considered in the light of current data about sex and hemisphere differences in the brain areas associated with language (Harasty et al., 1997) and sex differences in patients with Alzheimer's disease (Henderson and Buckwalter, 1994; Ripich et al., 1995).
|
Method |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionReferences |
|---|
Patients
The brains of 10 patients who were clinically followed after participating in a case–control study of Alzheimer's disease (Broe et al., 1990
) were collected, with consent from relatives, over a 3-year period. The criteria for inclusion in the study were the presence of severe language impairments, apparent during standardized testing interviews with neurologists or neuropsychologists, combined with pathologically confirmed Alzheimer's disease after post-mortem. The criterion for severe language impairment was rated retrospectively after clinical testing and interviews that included the Mini-Mental State Examination (Folstein et al., 1975), the Clinical Dementia Rating Scale (Berg, 1988) and neuropsychological assessment. All patients demonstrated severe cognitive difficulties, particularly in language and verbal memory, and all subjects fulfilled clinical criteria for probable Alzheimer's disease (McKhann et al., 1984) at the time of case recruitment. Testing results were available on all patients except one prior to death. In most cases testing was conducted within 1 year prior to death. All patients showed a progressive decline, all except one scoring 5 on the Clinical Dementia Rating Scale (Berg, 1988). This one patient scored 3 on this scale but demonstrated profound language, particularly semantic, impairment with the retention of some activities of daily living and self-help skills. She died of a myocardial infarction. All patients demonstrated language impairments typical of Alzheimer's disease. Symptoms of semantic dementia were apparent, with severe to profound naming difficulties both at the conversational level and during picture-naming and picture-matching tasks during testing. Both simple and complex commands were difficult for all patients, error rates on testing ranging from 100 to 60% incorrect. All patients also presented with a high percentage of errors on sentence repetition tasks as well as on simple counting and conversational tasks. Written tasks demonstrated some spelling and phonological errors while syntactic complexity and accuracy were severely reduced, as most patients could write only one- or two-word sentences.
In order to ensure that the patients analysed had severe language impairment, a rating scale of each patient's language abilities (Romero et al., 1990) was administered retrospectively on the testing and clinical interview data. The ratings were conducted by two speech–language pathologists/applied linguists, both of whom had a Ph.D. Inter-rater reliability for the ratings was high, with a point-to-point (within one category) agreement score of 95% between the two raters (reliability correlation coefficient was r = 0.6, P = 0.0039). All subjects demonstrated severe to extremely severe scores (3–5) on this scale for the semantic, syntactic and pragmatic–conceptual linguistic categories. Figure 1 illustrates the means and standard errors of the rating scale for each category of language.
|
Definitive diagnosis for Alzheimer's disease was based upon the examination of 10-µm paraffin sections from the frontal, cingulate, parietal and inferior temporal cortices, hippocampal formation, midbrain, pons, medulla oblongata and cerebellum, stained with haematoxylin and eosin, modified Bielschowsky silver (Garvey et al., 1991
) and tau and ubiquitin immunohistochemistry. Neuropathological examination of these sections confirmed the presence of Alzheimer's disease according to all current proposed criteria (National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, 1997).
The brains of 21 individuals free of known neurological and neuropathological abnormalities, using the criteria outlined above, were studied. No case was included where a history of cerebrovascular disease, trauma, heavy alcohol consumption or dementia was indicated. Case-matching across the two groups occurred for age (Alzheimer's disease: six males and four females, aged 49–92 years; controls: ten males and eleven females, aged 46–92 years). The post-mortem interval was 
36 h in all Alzheimer's disease and control cases (range 4–36 h, median 20 h). The study was approved by the Human Ethics Committees of the University of New South Wales and the University of Sydney under the Transplantation and Anatomy Act of New South Wales. Table 1 reports case details, including age, disease duration, sex, clinical dementia rating score, cause of death and brain weight.
|
Standardized brain preparation
As we have described previously (Double et al., 1996
; Harasty et al., 1997), all brains were embedded in agar and cut into 3-mm coronal slices perpendicular to the longitudinal axis, using a rotary slicer. There were no significant fixation rate changes between the Alzheimer's disease and control groups, or significant brain volume changes between fresh and fixed brain measurements. Each of the 3-mm slices was photographed and black-and-white prints (5 x 7 inches) were developed to the same magnification prior to their sequential numbering. Coronally sectioned brains were used as these have been shown to allow visualization of areas such as the planum temporale most consistently (Galaburda, 1993), and coronal sections are most commonly used for neuropathological evaluation.
Language-associated gyral regions
Cortical gyri generally considered critical and central for language include Broca's frontal area (Brodmann areas 44, 45 and 47) and the central portion of Wernicke's area in the superior temporal gyri (Broca, 1861; Wernicke, 1874). The superior temporal gyri are not exclusively involved in language-related tasks. However, the planum temporale is thought to be crucial for language-related functions while Heschl's gyrus immediately anterior to the planum temporale is the site of the primary auditory cortices (Dekaban, 1978; Ojemann and Mateer, 1979; Peterson et al., 1990; Kertesz, 1991; Wise, 1991; Demonet et al., 1993). In addition to these regions, a number of regions are considered to have language as well as non-language functions (Damasio et al., 1996; Habib and Demonet, 1996; Desgranges et al., 1998). These include Brodmann's parietal areas 37, 39 and 40, which are believed to have an integrative role attaching word meaning to sensory information, particularly orthographic information for area 39 (Luria, 1973; Damasio and Damasio, 1980; Posner et al., 1988; Zatorre et al., 1992). The inferior and middle temporal gyri are considered to be important in word memory and meaning (Luria, 1973; Benson, 1979; Ojemann and Mateer, 1979; Damasio and Damasio, 1980; Frackowiak et al., 1981; Mesulam, 1990; Kertesz, 1991; Boivin et al., 1992; Demonet et al., 1993; Gazzaniga, 1994). Evidence is accumulating suggesting that the left and right hemispheres are both involved in language functions, although to what extent and in which areas remain unclear (Code, 1987).
Volume analysis
Nine areas from different cortical lobes were chosen as a comprehensive but not exclusive sample of speech and language-associated regions (Brodmann areas 20, 21, anterior 22, 37, 39, 40, 41 and 42, and Broca's area, defined as Brodmann areas 44, 45 and 47; see Fig. 2). Because the right hemisphere is involved in non-linguistically based language (Ross and Mesulam, 1979; Ojemann and Whitacker, 1978; Code, 1987), both right and left cortical regions were sampled. The methods used to define the boundaries of these regions have been published previously with cytoarchitectural confirmation of the technique (Harasty et al., 1996b). The boundaries of the areas (Figs 2 and 4) were identified with the aid of Brodmann's map and other delineations (Witelson and Pallie, 1973; Galaburda et al., 1978; Witelson and Kigar, 1992). Standardization of the practical implementation of the sampling technique was reached by consensus by three researchers (J.A.H., G.M.H., J.J.K.). The anterior and posterior extent of these areas (Fig. 2) was determined with >90% agreement. When disagreement occurred a consensus of two of the three examiners was used. For all cases, volume analysis of cortical lobes has been published previously (Double et al., 1996).
|
|
Delineation of Heschl's gyri and the planum temporale subdivisions of the superior temporal gyri (Figs 2 and 4
) followed common practice as we have previously described (Harasty et al., 1997), the anterior border of the planum temporale being at the most anterior part of Heschl's sulcus (Steinmetz et al., 1991; Witelson and Kigar, 1992; Leonard et al., 1993), while the posterior border was defined as the posterior end of the Sylvian fissure (not including the ascending parietal wall) (Leonard et al., 1993). The superior temporal gyri were divided into three sections (Figs 2 and 4): the anterior superior temporal gyri, Heschl's gyri and the planum temporale. As previously described (Harasty et al., 1997), we did not separate areas 44, 45 and 47 of Broca's area for further analysis (Figs 2 and 4). Instead all three cytoarchitectural regions were included in a general volume named Broca's area, which was bounded by the lateral sulcus anteriorly (the internal landmark for reliable delineation was the genu of the corpus callosum) and by the ascending ramus of the lateral sulcus posteriorly (the internal landmark for reliable delineation was the crossing of the anterior commissure) (Harasty et al., 1996b). For the controls, volume analysis of the superior temporal gyri and Broca's area have been published previously (Harasty et al., 1997).
Few studies have identified the boundaries of the inferior and posterior temporoparietal regions: areas 40, 39 and 37 (Figs 2 and 4). We defined area 40 (including the supramarginal gyri) as the inferior parietal gyri above the lateral sulcus with the postcentral sulcus as the anterior border (the internal landmark for reliable delineation was the posterior border of the head of the caudate nucleus) and the posterior ramus of the Sylvian fissure as its posterior border (Figs 2 and 4). This posterior border separated area 40 from area 39 (the angular gyri). Area 39 was defined as the next posterior gyri with the superior parietal gyri located above (Figs 2 and 4). Area 37 was located inferior to area 39, both of these regions extending posteriorly to the parieto-occipital junction (the internal landmark for reliable delineation was the anterior part of the calcarine fissure).
The grey and white matter volumes in the speech and language-associated regions were calculated using a point-counting method as previously described (Double et al., 1996; Harasty et al., 1996b, 1997). Briefly, a grid of 21 x 31 points (each point equalling 0.62 mm2 of the slice area, the mean distance between slices being 3.31 ± 0.16 mm) was laid over each photograph, and (i) the number of points falling on each cortical region of interest and (ii) the total number of points falling within each brain slice were counted (mean points counted per cerebrum, 21 965 ± 716). Measurements were conducted by one examiner blind to the study aim and to case gender. Volumes were determined by applying Cavalieri's principle [the number of points multiplied by the slice thickness multiplied by the area of each point (Coggeshaw, 1992)]. Repeated measures gave <5% variation and the inter-rater correlation was r = 0.876. The proportion of the total cerebrum volume of each of the measured areas was determined.
Statistical analysis was performed using Statview (Abacus, 1991). Analysis of variance was chosen, as this test provides the most robust assessment of groupdifferences using interval data. It compares the relationship of nominal variables such as sex andhemisphere with interval volume data from each region, and the assumption of normal distribution ofbrain volume was met. Age was controlled by age-matching across the two groups. At test showed no significant differences (t = 0.54,P = 0.6) in this variable. Due to this finding and previous work showing that age is a less importantcontributor to volume and neuron number than sex (Pakkenberg and Gundersen, 1997), age was not included as a separate variable. Therefore, only differences between groups, sexes and hemispheres were analysed using three-way analysis of variance for repeated measures (Gardner and Altman, 1989). The percentage difference between the mean of the control group and the mean of the Alzheimer'sdisease group was used to determine the relative severity of involvement of each region (Harastyet al., 1996a). The mean ± standard deviation is given for all variables and aP value of <0.05 was accepted as statistically significant. A Kruskal–Wallis ranking testwas used to determine if the amount of atrophy differed in severity between the different regions.
The relationships between the volumes of the grey and white matter and the age at death, age atdisease onset and duration of the disease were examined using multiple regression analysis. Thistype of analysis was used as it provides detailed robust analysis of the relationship between twoindependent interval level variables (Minium, 1978;Ott, 1988;Gardner and Altman, 1989). As the clinical dementia and linguistic rating scores were on ordinal scales, with all scores withina narrow range, these measures were used as diagnostic variables for case selection only.
|
Results |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionReferences |
|---|
Effects of hemisphere and gender
The majority of the language-associated gyri were significantly affected by the disease processwithout the interaction of hemisphere and gender. There were no size differences betweenhemispheres throughout all the speech and language-associated regions in either the controlpatients (also reported inHarastyet al., 1997
) or the patients with Alzheimer's disease, indicating symmetry in the disease process. There were differing gender effects throughout the speech and language-associated regions. In themiddle and anterior superior temporal gyri and area 40, the cortex and white matter of the maleswere significantly larger than those of the females in both Alzheimer's disease subjects andcontrols. This is not unexpected considering the overall larger size of male brains. However, therewas a sex x disease interaction in the anterior superior temporal gyri (grey matter: diseasex sex,P = 0.004; sex x side,P = 0.25; disease x sex x side,P = 0.5; white matter: disease x sex,P = 0.01; sex x side,P = 0.2; disease x sex x side,P = 0.51). In this area, the females with Alzheimer's disease had a 59% greater gyral loss than the males. Indeed, the male patients with Alzheimer's disease did not show reduced volumes compared with the control group of males.
In summary, no sex differences or sex x diagnosis interactions in regional volumes were discerned in the majority of the speech and language-associated regions, suggesting that in most of these cortical regions the disease affected the two sexes in a similar manner. However, the disease process did differentially affect the anterior superior temporal gyri in the female patients while sparing this region in the male patients.
Disease effects
Of the nine speech and language-associated regions, six showed significant cortical atrophy compared with the age-matched controls. Two of the three parietal lobe regions—area 37 in the temporoparietal junction and area 40 (including the supramarginal gyri)—were affected. In the temporal lobe, both the middle and the inferior temporal gyri were areas with significant cortical atrophy. Only two of the three sections of the superior temporal gyri—the anterior section and the planum temporale—were significantly reduced compared with controls. There were no significant ranking differences between these different atrophied areas (P = 0.47). It was not surprising to find that the white matter underlying these gyri was also significantly affected. There were no significant relationships between the atrophy in any of these regions and the duration of the disease, age at disease onset or age at death (P > 0.05). Figure 3 summarizes these results.
|
Although the planum temporale was affected, the neighbouring area, the primary hearing region of the superior temporal gyri, Heschl's gyri, showed no significant differences in the grey or white matter volumes compared with controls. In this sample, area 39 (the angular gyri) also did not show significant atrophy of either the grey or the white matter. The language-associated regions of the frontal lobe, the inferior frontal cortices, also did not show significant atrophy compared with the control group.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionReferences |
|---|
The present study is the first to analyse the volumes of language-associated specific cortical gyri in post-mortem patients with confirmed Alzheimer's disease. The results show that atrophy is not global but gyrus-specific even at end-stage Alzheimer's disease. Atrophy reflects aspects of the types of clinical language and semantic dementia impairments described in Alzheimer's disease. In addition, atrophic changes are symmetrical across hemispheres and generally affect the two sexes in a similar manner in most of the language-associated regions.
Language-associated gyral atrophy
The language-associated cortical regions were differentially affected in the patients analysed. Indeed, contrary to views of Alzheimer's disease as a global deterioration of the cortex (Mann, 1991), it appears that some regions, e.g. Broca's area and the primary association area for hearing, Heschl's gyri, showed little or no overall gyral atrophy in this sample of patients. A lack of atrophy in these areas reflects functional findings. Patients with probable Alzheimer's disease rarely show non-fluent language difficulties (Greene et al., 1996b), and this may be mirrored by the lack of atrophy seen in Broca's area. Data have also been reported on the sparing of hearing skills and phonologic distinction in Alzheimer's disease (Biassou et al., 1995), and these data reflect our findings of lack of atrophy in Heschl's gyrus. When viewed together, the pattern of cortical loss seen in our sample centred on five regions in the temporal and parietal lobe (area 37, the inferior and middle temporal gyri, the anterior superior temporal gyri, the planum temporale and area 40, which includes the supramarginal gyri). These regions are situated next to each other. Two temporoparietal regions were spared, area 39 (angular gyri) and Heschl's gyri.
There have been few post-mortem studies which have analysed volume changes across a range of gyri. Our recent study of lobar atrophy (Double et al., 1996) confirms previous in vivo volume studies which indicate that temporal lobe structures are markedly affected (Killiany et al., 1993; Laakso et al., 1995; Lehtovirta et al., 1995; Shear et al., 1995; Soininen et al., 1995), although some studies have shown that frontal areas can also be severely affected (Obara et al., 1994). Studies examining blood flow patterns consistently find what is now considered the `classical pattern' of temporoparietal hypometabolism in patients with probable Alzheimer's disease (Frackowiak et al., 1981; Kumar et al., 1991; Powers et al., 1992; Parks et al., 1993; Greene et al., 1996a). The present study has identified more specifically which of the temporoparietal regions are atrophic in a sample of patients with confirmed end-stage Alzheimer's disease. Surprisingly, atrophy was found to be specific to particular language-associated gyri rather than being demonstrated across all cortical areas associated with language, some gyri showing no dissolution at the end stage. These data do not support conceptualizations of Alzheimer's disease as a widespread global disease.
Of the language areas affected in Alzheimer's disease, the additional involvement of the anterior superior temporal gyri in females with Alzheimer's disease is a unique finding. It is interesting to speculate that this finding relates to previous data showing that women with Alzheimer's disease have greater language difficulties than men (Henderson and Buckwalter, 1994; Ripich et al., 1995). Unfortunately, few past studies of Alzheimer's disease specifically investigated gender as a separate variable in the data analysis. Gender differences in the prevalence and risk for Alzheimer's disease have been noted recently (Lautenschlager et al., 1996; Payami et al., 1996). Data have also been reported suggesting that, when confounding demographic variables are controlled, women with probable Alzheimer's disease do more poorly on a composite neuropsychological battery than men (Henderson and Buckwalter, 1994). Differences in the language-related subtests of verbal fluency, naming tasks and delayed recall subsets accounted for these differences. However, the present finding of selective tissue loss appears unique. There is increasing evidence that the anterior superior temporal region plays a role in word-finding (Langfitt and Rausch, 1997). The relationship between the current findings of differential atrophy and reports of gender differences in the clinical manifestations of Alzheimer's disease needs to be investigated further.
Relationship between the gyral atrophy and language impairments
These data show that, even in end stage Alzheimer's disease, distinct language-associated gyri are spared while others show severe atrophy. This suggests that the conceptualization that Alzheimer's disease leads to a widespread type of generalized atrophy which affects all brain systems and networks equally at the end stage are unlikely. Instead, discrete and localized brain networks are affected while others, often both functional and locational neighbours, remain without atrophy. These data appear to support one of the two competing theories about semantic category dissolution, the one favoured by Garrard et al. (1998), in which semantic category breakdown reflects localized brain region distinctions. We would also suggest that dissolution in more general aspects of language skills, such as fluent compared with non-fluent aphasias, may be subserved by the breakdown of specific brain regions and the lack of breakdown in others.
The cortical areas primarily affected in our sample appear to subserve the network of object-naming, word and phonological retrieval and recognition, and general semantic skills (Mesulam, 1990). It is possible that connections between some of these regions consist of more frequently used neuronal assemblies. Considering the network of skills needed when retrieving the names and functions of seen objects (area 37, inferior and middle temporal gyri, planum temporale), including the retrieval of the phonological structure of words (Coltheart, 1987), increased utilization of the pathways affected is a plausible explanation. If we assume that the entorhinal cortex of the parahippocampal gyri and then area 37 and the inferior temporal gyri are the initial sites for this disease, as has been suggested (Braak and Braak, 1991), then the cortical assemblies most directly related to the network subserving semantic knowledge and retrieval appear to deteriorate. It has been shown that area 37 subserves visual object identification (Sergent et al., 1992; Smith et al., 1996) while the middle and anterior superior temporal gyri participate in object meaning, that the planum temporale is involved in the phonological structure of the word image and that the supramarginal gyri in area 40 relates to the object's function within space (Neville and Bavelier, 1998). Thus, the pattern of gyral atrophy identified in the patients with Alzheimer's disease correlates with their most prominent language disorder.
There have been some very recent data from in vivo PET and MRI which support the discrete involvement of separate and specific regions of the temporal and frontal cortex in particular language functions. Kohler et al. (1998) suggest that some brain regions are involved with domain-specific tasks such as spatial location and object identity. These regions include the right middle occipital gyrus, the supramarginal gyrus and the superior temporal sulcus, while other brain regions, such as the bilateral superior temporal cortex and the bilateral middle and inferior frontal gyri, are important for general encoding and retrieval across memory domains. Mesulam (1998) reported evidence from all functional imaging studies investigating naming within different modalities. He concluded that naming colours, actions, familiar faces and animals selectively activates separate and discrete regions of the temporal lobe.
While our study is the first to analyse regional gyral atrophy, the data are consistent with previous lobar studies (Double et al., 1996) and lend support to the suggestions of Greene, Hodges and Patterson that the network underlying semantic dementia is related to anterior and posterior regions of the temporal and parietal lobes (Patterson et al., 1994; Greene et al., 1996b). Although there have been few studies of the volume of the angular gyri in post-mortem samples, both pathological and metabolic studies of the inferior parietal lobe have shown this area to be significantly affected in many cases of Alzheimer's disease (Frackowiak et al., 1981; Kumar et al., 1991; Powers et al., 1992; Parks et al., 1993). In contrast, we did not see dramatic atrophy in this part of the inferior parietal lobe. Parietal atrophy was confined to the inferior temporoparietal junction, Brodmann area 37 and to a lesser extent to area 40 (including the supramarginal gyri), the angular gyri being relatively spared. This specific finding contrasts with those obtained using metabolic measurements such as from SPECT and PET, which have shown a role for both the supramarginal and the angular gyri in the reading and writing disturbances in Alzheimer's disease (Penniello et al., 1995). It is interesting to note that recent data have suggested that dysgraphia is not a constant feature of Alzheimer's disease and that when deficits are apparent they take the form of mild surface dysgraphia (Hughes et al., 1997). The lack of gross atrophy in our sample supports the concept of only a mild deficit in functions subserved by area 39 (the angular gyri). A recent study analysing very mild cases of probable Alzheimer's disease (Greene and Hodges, 1996) suggests that the pattern of brain dysfunction (measured using SPECT) and language impairment (measured using detailed neuropsychological batteries) early in the disease concentrates in the left posterior temporal lobe, right superior frontal lobe and right posterior temporal lobe. This work suggests that the reproducible parietal involvement documented in Alzheimer's disease must occur later in the disease process. Alternatively, disconnection from other dysfunctional language-associated regions may explain significant deficits in metabolic measures.
Our data do suggest that particular brain regions appear to subserve discrete or disconnected types of language functions. However, while this is the case, it is likely that language functions are based on a network of connections between these regions (Pulvermuller, 1996; Mesulam, 1998). Groups of localized cell assemblies may be networked together in a nested hierarchical tree of increasingly large cell aggregates (Harasty et al., 1994). Loss of fundamental cell assemblies in discrete areas then affects cell assembly recruitment and thus the holistic functioning of the network.
In conclusion, data presented in this study provide the first pathological evidence that discrete language impairments reflect selective involvement of particular temporal and parietal gyri in end-stage Alzheimer's disease. We suggest that these data do not necessarily contravene the view that the neural substrate of these functions is networked (Mesulam, 1990; Pulvermuller, 1996) but emphasize a level of gyral localization within the large-scale networks for certain functions. Further research identifying the precise localization of neuronal loss of function in the gyri identified here may provide knowledge of the cellular basis for the pattern of language dissolution in Alzheimer's disease.
|
Acknowledgments |
|---|
We wish to thank Heidi Cartwright for illustrations and figures, Xan Phung and Heather McCann for research assistance, Professor Broe and Dr Bill Brooks, Concord Hospital, Centre for Research into Ageing for essential assistance with patients, Dr Alison Ferguson for ratings on the linguistic scale and two anonymous reviewers and the editor for beneficial changes to the manuscript. We offer especial thanks to Professor John Hodges, University of Cambridge, UK for his continuing inspiration. This work was supported by the University of New South Wales Medical Foundation, the National Health and Medical Research Council and the Medical Foundation of the University of Sydney and the Faculty of Health Sciences, The University of Sydney.
|
References |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionReferences |
|---|
Abacus. Statview. Berkeley (CA): Abacus Concepts; 1991.
Aboitiz F, Garcia VR. The evolutionary origin of the language areas in the human brain. A neuroanatomical perspective. [Review]. Brain Res Brain Res Rev 1997; 25: 381–96.[Medline]
Appell J, Kertesz A, Fisman M. A study of language functioning in Alzheimer patients. Brain Lang 1982; 17: 73–91.[Web of Science][Medline]
Au R, Albert ML, Obler LK. The relation of aphasia to dementia. Aphasiology 1988; 2: 161–73.
Bartenstein P, Minoshima S, Hirsch C, Buch K, Willoch F, Mosch D, et al. Quantitative assessment of cerebral blood flow in patients with Alzheimer's disease by SPECT. J Nucl Med 1997; 38: 1095–101.
Bayles KA, Tomoeda CK, Trosset MW. Alzheimer's disease: effects on language. Dev Neuropsychol 1993; 9: 131–60.[Web of Science]
Benson DF. Aphasia, alexia and agraphia. New York: Churchill Livingstone; 1979.
Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988; 24: 637–9.[Web of Science][Medline]
Biassou N, Grossman M, Onishi K, Mickanin J, Hughes E, Robinson KM, et al. Phonologic processing deficits in Alzheimer's disease. Neurology 1995; 45: 2165–9.
Boivin MJ, Giordani B, Berent S, Amato DA, Lehtinen S, Koeppe RA, et al. Verbal fluency and positron emission tomographic mapping of regional cerebral glucose metabolism. Cortex 1992; 28: 231–9.[Web of Science][Medline]
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. [Review]. Acta Neuropathol [Berl] 1991; 82: 239–59.[Medline]
Broca PP. Remarques sur le siège de la faculté du language articulé, suivie d'une observation d'aphémie (perte de la parole). Bull Soc Anat Paris 1861; 36: 330–57.
Broe GA, Henderson AS, Creasey H, McCusker E, Korton AE, Jorm AF, et al. A case–control study of Alzheimer's disease in Australia. Neurology 1990; 40: 1698–707.
Code C. Language, aphasia and the right hemisphere. Chichester: Wiley; 1987.
Code C, Lodge B. Language in dementia of recent referral. Age Ageing 1987; 16: 366–72.
Coggeshaw RE. A consideration of neural counting methods. Trends Neurosci 1982; 15: 9–13.
Coltheart M, Sartor G, Job R. The cognitive neuropsychology of language. London: Lawrence Erlbaum; 1987.
Cummings JL, Benson F, Hill MA, Read S. Aphasia in dementia of the Alzheimer type. Neurology 1985; 35: 394–7.
Damasio H, Damasio AR. The anatomical basis of conduction aphasia. Brain 1980; 103: 337–50.
Damasio AR, Damasio H. Brain and language. Sci Am 1992; 267: 88–95.[Medline]
Damasio H, Grabowski TJ, Tranel D, Hichwa RD, Damasio AR. A neural basis for lexical retrieval [see comments] [published erratum appears in Nature 1996; 381: 810]. Nature 1996; 380: 499–505. Comment in: Nature 1996; 380: 485–6.[Medline]
Daum I, Riesch G, Sartori G, Birbaumer N. Semantic memory impairment in Alzheimer's disease. J Clin Exp Neuropsychol 1996; 18: 648–65.[Web of Science][Medline]
Dekaban AS. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 1978; 4: 345–56.[Web of Science][Medline]
Demonet J-F, Wise R, Frackowiak RSJ. Language functions explored in normal subjects by positron emission tomography: a critical review. Hum Brain Mapp 1993; 1: 39–47.
Desgranges B, Eustache F, Rioux P, de la Sayette V, Lechevalier B. Memory disorders in Alzheimer's disease and the organization of human memory. Cortex 1996; 32: 387–412.[Web of Science][Medline]
Desgranges B, Baron J-C, de la Sayette V, Petit-Taboue M-C, Benali K, Landeau B, et al. The neural substrates of memory systems impairment in Alzheimer's disease. A PET study of resting brain glucose utilization. Brain 1998; 121: 611–31.
Deweer B, Lehericy S, Pillon B, Baulac M, Chiras J, Marsault C, et al. Memory disorders in probable Alzheimer's disease: the role of hippocampal atrophy as shown with MRI. J Neurol Neurosurg Psychiatry 1995; 58: 590–7.
Double KL, Halliday GM, Kril JJ, Harasty JA, Cullen K, Brooks WS, et al. Topography of brain atrophy during normal aging and Alzheimer's disease. Neurobiol Aging 1996; 17: 513–21.[Web of Science][Medline]
Esiri, MM, Pearson, RC, Powell, TP. The cortex of the primary auditory area in Alzheimer's disease. Brain Res 1986; 366: 385–7.[Web of Science][Medline]
Folstein MF, Folstein SE, McHugh PR. `Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98.[Web of Science][Medline]
Frackowiak RS, Pozzilli C, Legg NJ, Du Boulay GH, Marshall J, Lenzi GL, et al. Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen 15 and positron tomography. Brain 1981; 104: 753–78.
Galaburda AM. The planum temporale [editorial] [see comments]. Arch Neurol 1993; 50: 457. Comment in: Arch Neurol 1994; 51: 540.
Galaburda AM, Sanides F, Geschwind N. Human brain. Cytoarchitectonic left–right asymmetries in the temporal speech region. Arch Neurol 1978; 35: 812–7.
Gardner MJ, Altman DG. Statistics with confidence. London: British Medical Journal; 1989.
Garrard P, Patterson K, Watson PC, Hodges JR. Category specific semantic loss in dementia of Alzheimer's type. Brain 1998; 121: 633–46.
Garvey W, Fathi A, Bigelow F, Jimenez CL, Carpenter BF. Rapid, reliable and economical silver stain for neurofibrillary tangles and senile plaques. J Histotech 1991; 14: 39–42.
Gazzaniga MS. Language and the cerebral hemispheres. Discuss Neurosci 1994; 10: 106–9.
Gonnerman LM, Andersen ES, Devlin JT, Kempler D, Seidenberg MS. Double dissociation of semantic categories in Alzheimer's disease. Brain Lang 1997; 57: 254–79.[Web of Science][Medline]
Greene JD, Hodges JR. The fractionation of remote memory. Evidence from a longitudinal study of dementia of Alzheimer type. Brain 1996; 119: 129–42.
Greene JD, Miles K, Hodges JR. Neuropsychology of memory and SPECT in the diagnosis and staging of dementia of Alzheimer type. J Neurol 1996a; 243: 175–90.[Web of Science][Medline]
Greene JD, Patterson K, Xuereb J, Hodges JR. Alzheimer disease and nonfluent progressive aphasia. [Review]. Arch Neurol 1996b; 53: 1072–8.
Grossman M, D'Esposito M, Hughes E, Onishi K, Biassou N, White-Devine T, et al. Language comprehension profiles in Alzheimer's disease, multi-infarct dementia, and frontotemporal degeneration. Neurology 1996; 47: 183–9.
Grossman M, Payer F, Onishi K, D'Esposito M, Morrison D, Sadek A, et al. Language comprehension and regional cerebral defects in frontotemporal degeneration and Alzheimer's disease. Neurology 1998; 50: 157–63.
Habib M, Demonet JF. Cognitive neuroanatomy of language: the contribution of functional neuroimaging. Aphasiology 1996; 10: 217–34.[Web of Science]
Harasty J, Harasty CD, Halliday G. Language: a dynamic network of `inherited' hierarchical neural assemblies? Proc Aust Neurosci Soc 1994; 5: 97.
Harasty JA, Halliday GM, Code C, Brooks WS. Quantification of cortical atrophy in a case of progressive fluent aphasia. Brain 1996a; 119: 181–90.
Harasty J, Halliday GM, Kril JJ. Reproducible sampling regimen for specific cortical regions: application to speech-associated areas. J Neurosci Methods 1996b; 67: 43–51.[Web of Science][Medline]
Harasty J, Double KL, Halliday GM, Kril JJ, McRitchie DA. Language-associated cortical regions are proportionally larger in the female brain. Arch Neurol 1997; 54: 171–6.
Hart S. Language and dementia: a review. [Review]. Psychol Med 1988; 18: 99–112.[Web of Science][Medline]
Henderson VW, Buckwalter JG. Cognitive deficits of men and women with Alzheimer's disease. Neurology 1994; 44: 90–6.
Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, et al. Regional hypometabolism related to language disturbance in Alzheimer's disease. Dement Geriatr Cogn Disord 1998; 9: 68–73.[Web of Science][Medline]
Hodges JR, Patterson K. Is semantic memory consistently impaired early in the course of Alzheimer's disease? Neuroanatomical and diagnostic implications. Neuropsychologia 1995; 33: 441–59.[Web of Science][Medline]
Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia. Brain 1992; 115: 1783–806.
Hughes JC, Graham N, Patterson K, Hodges JR. Dysgraphia in mild dementia of Alzheimer's type. Neuropsychologia 1997; 35: 33–545.
Jack CR Jr, Petersen RC, O'Brien PC, Tangalos EG. MR-based hippocampal volumetry in the diagnosis of Alzheimer's disease. Neurology 1992; 42: 183–8.
Kertesz A. Language cortex. Aphasiology 1991; 5: 207–34.[Web of Science]
Killiany RJ, Moss MB, Albert MS, Sandor T, Tieman J, Jolesz F. Temporal lobe regions on magnetic resonance imaging identify patients with early Alzheimer's disease. Arch Neurol 1993; 50: 949–54.
Kohler S, Moscovitch M, Winocur G, Houle S, McIntosh AR. Networks of domain-specific and general regions involved in episodic memory for spatial location and object identity. Neuropsychologia 1998; 36: 129–42.[Web of Science][Medline]
Kumar A, Schapiro MB, Grady C, Haxby JV, Wagner E, Salerno JA, et al. High-resolution PET studies in Alzheimer's disease. Neuropsychopharmacology 1991; 4: 35–46.[Web of Science][Medline]
Laakso MP, Soininen H, Partanen K, Helkala E-L, Hartikainen P, Vaino P, et al. Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer's disease: correlation with memory functions. J Neural Transm Park Dis Dement Sect 1995; 9: 73–86.[Web of Science][Medline]
Lambon Ralph MA, Patterson K, Hodges JR. The relationship between naming and semantic knowledge for different categories in dementia of Alzheimer's type. Neuropsychologia 1997; 35: 1251–60.[Web of Science][Medline]
Langfitt JT, Rausch R. Word-finding deficits persist after left anterotemporal lobectomy. Arch Neurol 1997; 53: 72–6.[Web of Science]
Lautenschlager NT, Cupples LA, Rao VS, Auerbach SA, Becker R, Burke J, et al. Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: what is in store for the oldest old? Neurology 1996; 46: 641–50.
Lehtovirta M, Laakso MP, Soininen H, Helisalmi S, Mannermaa A, Helkala E-L, et al. Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes. Neuroscience 1995; 67: 65–72.[Web of Science][Medline]
Leonard CM, Voeller KK, Lombardino LJ, Morris MK, Hynd GW, Alexander AW, et al. Anomalous cerebral structure in dyslexia revealed with magnetic resonance imaging [see comments]. Arch Neurol 1993; 50: 461–9. Comment in: Arch Neurol 1994; 51: 540.
Luria AR. The working brain: an introduction to neuropsychology. Harmondsworth: Penguin; 1973.
Mann DM. (1991) The topographic distribution of brain atrophy in Alzheimer's disease. Acta Neuropathol (Berl) 1991; 83: 81–6.[Medline]
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlian EM. Clinical diagnosis of Alzheimer's disease. Neurology 1984; 34: 939–44.
Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. [Review]. Ann Neurol 1990; 28: 597–613.[Web of Science][Medline]
Mesulam M-M. From sensation to cognition. [Review]. Brain 1998; 121: 1013–52.
Minium EW. Statistical reasoning in psychology and education. New York: John Wiley; 1978.
Nagy Z, Jobst KA, Esiri MM, Morris JH, King EM-F, MacDonald B, et al. Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer's disease: clinicopathologic correlations using three sets of pathologic diagnostic criteria. Dementia 1996; 7: 76–81.
Neville HJ, Bavelier D. Neural organization and plasticity of language. [Review]. Curr Opin Neurobiol 1998; 8: 254–8.[Web of Science][Medline]
National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's disease. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. [Review]. Neurobiol Aging 1997; 18 (4 Suppl): S1–2.
Obara K, Meyer JS, Mortel KF, Muramatsu K. Cognitive declines correlate with decreased cortical volume and perfusion in dementia of Alzheimer type. J Neurol Sci 1994; 127: 96–102.[Web of Science][Medline]
Obler LK, Albert ML. Language in the elderly aphasic and in the dementing patient. In: Sarno MT, editor. Acquired aphasia. New York: Academic Press; 1981. p. 385–97.
Ojemann G, Mateer C. Human language cortex: localization of memory, syntax, and sequential motor-phoneme identification systems. Science 1979; 205: 1401–3.
Ojemann GA, Whitaker HA. Language localization and variability. Brain Lang 1978; 6: 239–60.[Web of Science][Medline]
Ott L. An introduction to statistical methods and data analysis. Princeton: P.W.S. Kent; 1988.
Pakkenberg B, Gundersen HJ. Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 1997; 384: 312–20.[Web of Science][Medline]
Parks RW, Haxby JV, Grady CL. Positron emission tomography in Alzheimer's disease. In: Parks RW, Zec RF, Wilson RS, editors. Neuropsychology of Alzheimer's disease and other dementias. New York: Oxford University Press, 1993. p. 459–88.
Patterson K, Graham N, Hodges JR. Reading in dementia of the Alzheimer type: a preserved ability? Neuropsychology 1994; 8: 395–407.
Payami H, Zareparsi S, Montee KR, Sexton GJ, Kaye JA, Bird TD, et al. Gender differences in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 1996; 58: 803–11.[Web of Science][Medline]
Penniello M-J, Lambert J, Eustache F, Petit-Taboue MC, Barre L, Viader F, et al. A PET study of the functional neuroanatomy of writing impairment in Alzheimer's disease. The role of the left supramarginal and left angular gyri. Brain 1995; 118: 697–706.
Petersen SE, Fox PT, Snyder AZ, Raichle ME. Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science 1990; 249: 1041–4.
Posner MI, Petersen SE, Fox PT, Raichle ME. Localization of cognitive operations in the human brain. [Review]. Science 1988; 240: 1627–31.
Powers WJ, Perlmutter JS, Videen TO, Herscovitch P, Griffeth LK, Royal HD, et al. Blinded clinical evaluation of positron emission tomography for diagnosis of probable Alzheimer's disease. Neurology 1992; 42: 765–70.
Pulvermuller F. Hebb's concept of cell assemblies and the psychophysiology of word processing. [Review]. Psychophysiology 1996; 33: 317–33.[Web of Science][Medline]
Ripich DN, Petrill SA, Whitehouse PJ, Ziol EW. Gender differences in language of AD patients: a longitudinal study. Neurology 1995; 45: 299–302.
Romero B, Kurz A, Haupt M, Zimmer R, Lauter H, Pulvermuller F, et al. Diagnostic significance of language evaluation in early stages of Alzheimer's disease. In: Mauer K, Riederer P, Beckmann H, editors. New York: Springer-Verlag; 1990. p. 393–9.
Ross ED, Mesulam M-M. Dominant language functions of the right hemisphere? Prosody and emotional gesturing. Arch Neurol 1979; 36: 144–8.
Ross SJ, Graham N, Stuart-Green L, Prins M, Xuereb J, Patterson K, et al. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1996; 61: 388–95.
Sergent J, Ohta S, MacDonald B. Functional neuroanatomy of face and object processing. Brain 1992; 115: 15–36.
Shear PK, Sullivan EV, Mathalon DH, Lim KO, Davis LF, Yesavage JA, et al. Longitudinal volumetric computed tomographic analysis of regional brain changes in normal aging and Alzheimer's disease. Arch Neurol 1995; 52: 392–402.
Smith CD, Andersen AH, Chen Q, Blonder LX, Kirsch JE, Avison MJ. Cortical activation in confrontation naming. Neuroreport 1996; 7: 781–5.[Web of Science][Medline]
Soininen HS, Partanen K, Pitkanen A, Vainio P, Hanninen T, Hallikainen M, et al. Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age-associated memory impairment: correlation to visual and verbal memory. Neurology 1994; 44: 1660–8.
Soininen H, Helkala E-L, Kuikka J, Hartikainen P, Lehtovirta M, Riekkinen PJ Sr. Regional cerebral blood flow measured by 99mTc-HMPAO SPECT differs in subgroups of Alzheimer's disease. J Neural Transm Park Dis Dement Sect 1995; 9: 95–109.[Web of Science][Medline]
Steinmetz H, Volkmann J, Jancke L, Freund H-J. Anatomical left–right asymmetry of language-related temporal cortex is different in left- and right-handers. Ann Neurol 1991; 29: 315–9.[Web of Science][Medline]
Vargha-Khadem F, Gadian DG, Watkins KE, Connelly A, Van Paesschen W, Mishkin M. Differential effects of early hippocampal pathology on episodic and semantic memory [see comments] [published erratum appears in Science 1997; 277: 1117]. Science 1997; 277: 376–380. Comment in: Science 1997; 277: 330–1.
Warrington EK, McCarthy R. Category specific access dysphasia. Brain 1983; 106: 859–78.
Wernicke K. Der aphasische symptomenkomplex. In: Cohen RS, Wartofsky MW, editors. Boston studies in the philosophy of science, Vol. 4. 1874. p. 34–97.
Wise RJS. The anatomy of single word processing: activation studies with positron emission tomography. J Neuroling 1991; 6: 273–84.
Witelson SF, Kigar DL. Sylvian fissure morphology and asymmetry in men and women: bilateral differences in relation to handedness in men. J Comp Neurol 1992; 323: 326–40.[Web of Science][Medline]
Witelson SF, Pallie W. Left hemisphere specialization for language in the newborn: neuroanatomical evidence of asymmetry. Brain 1973; 96: 641–46.
Zatorre RJ, Evans AC, Meyer E, Gjedde A. Lateralization of phonetic and pitch discrimination in speech processing. Science 1992; 256: 846–9.
Received July, 1998. Revised November 2, 1998. Accepted November 16, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Grossman, S. X. Xie, D. J. Libon, X. Wang, L. Massimo, P. Moore, L. Vesely, R. Berkowitz, A. Chatterjee, H. B. Coslett, et al. Longitudinal decline in autopsy-defined frontotemporal lobar degeneration Neurology, May 27, 2008; 70(22): 2036 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schofield, C. Kersaitis, C. E. Shepherd, J. J. Kril, and G. M. Halliday Severity of gliosis in Pick's disease and frontotemporal lobar degeneration: tau-positive glia differentiate these disorders Brain, April 1, 2003; 126(4): 827 - 840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.A. Harasty, G.M. Halliday, J. Xuereb, K. Croot, H. Bennett, and J.R. Hodges Cortical degeneration associated with phonologic and semantic language impairments in AD Neurology, April 10, 2001; 56(7): 944 - 950. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||